The pH-dependent vesicle membrane binding property of chromogranin A appears to be of fundamental physiological importance with regard to the potential roles of chromogranin A in secretory vesicle biogenesis. This is particularly true in segregating secretory vesicle membranes from other membranes in the trans-Golgi network, and also in transmitting extravehicular signals, such as inositol 1,4,5-triphosphate (IP3) or inositol 1,3,4,5-tetrakisphosphate, for Ca2+ release or uptake to the inside of vesicles. Several vesicle matrix proteins of the secretory vesicles, including chromogranins A and B, bound to the vesicle membrane at the intravesicular pH of 5.5 and were freed from it when the pH was raised to a near physiological level of 7.5. Further, chromogranin A is shown to interact with several integral membrane proteins of the secretory vesicles at pH 5.5, but not at pH 7.5. One of the chromogranin A interacting membrane proteins had a size of 260 kDa and reacted with the IP3 receptor antibody. This result suggested the existence of the IP3 receptor/Ca2+ channel in the vesicle membrane and also the existence of direct communication between chromogranin A and the IP3 receptor/Ca2+ channel. In addition, the pH-dependent interaction of chromogranin A with integral membrane proteins implies an important role for chromogranin A in the sorting process of the vesicle membrane proteins during vesicle biogenesis in the trans-Golgi network. Further study has shown that one of the intraluminal loop domains of the IP3 receptor/Ca2+ channel interacts with chromogranin A at the intravesicular pH of 5.5, suggesting the importance of the intraluminal loop domain in transmitting Ca2+ mobilization signals to chromogranin A.